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Dwight A. Towler, MD, PhD Associate Professor of Medicine,
Dr. Towler received his MD/PhD from Washington University School of Medicine, St. Louis, MO. He completed a residency in Internal Medicine at Barnes-Jewish Hospital and a residency in Endocrinology, Diabetes and Metabolism at Washington University. In addition to his academic career, Dr. Towler has spent four years in the pharmaceutical industry, most recently as the Senior Director of Bone Biology and Osteoporosis Research at Merck Research Laboratories. Dr. Towler's NIH-supported research emphasizes transcription factor biology and signal transcription relevant to bone formation and vascular calcification. Clinically, he specializes in internal medicine, vascular endocrinology, and bone and mineral diseases. During his career, he has been awarded the 1996-1999 Charles E. Culpeper Medical Science Scholar; the 2000 Fuller Albright Award from the American Society for Bone and Mineral Research; and the 2004 American Society for Clinical Investigation. In 2004 Dr. Towler was awarded the Ira M. Lang Chair in Medicine and served on the Editorial Board of the Journal of Bone and Mineral Research; 2004. He is a Regular Member of the Skeletal Biology Development and Disease NIH Study Section, 2005. Research Interests The mechanisms whereby multipotent mesenchymal cells initiate osteogenic transcriptional responses to morphogenetic, metabolic, and mechanical cues are poorly understood. Msx2 and Runx2 have emerged as two key transcriptional regulators of osteoblast-dependent extracellular matrix mineralization. Runx2/Cbfa1 globally regulates both intramembranous and endochondral bone formation. Msx2, by contrast, functions to regulate intramembranous ossification during craniofacial development. The osteocalcin (OC) gene has proven useful for detailed studies of osteoblast transcription. Dr. Towler and his group have identified a regulatory region in the OC promoter that entrains expression to activated fibroblast growth factor receptor 2 (FGFR2) signaling, a receptor tyrosine kinase cascade necessary for normal skeletal growth and mineralization. This region, the OCFRE, is activated by Runx2, a specific Ku antigen complex, and a novel Msx2 co-regulator, MINT (spen). Msx2 controls this complex via cell-autonomous, antagonistic protein-protein interactions with all three of these components. They are currently defining how MINT and Runx2 interact to control osteoblast gene transcription. Of note, an osteogenic gene regulatory program is also recruited during the macrovascular (atherosclerotic, medial artery, cardiac valve) calcification associated with diabetes. For diabetic medial calcification, this proceeds in part via upregulation of aortic BMP2 and the induction of Msx2 in peri-arterial adventitial myofibroblasts. They have identified that Msx2 promotes osteogenic lineage allocation of vascular osteoprogenitors via paracrine canonical Wnt / Dkk1 signaling. Of note, diabetes also upregulates vascular smooth muscle expression of the bone matrix protein osteopontin. This occurs via a bipartite USF1-AP1 element that conveys hyperglycemia-induced gene transcription. OPN promotes VSMC MMP9 activation and matrix turnover via a paracrine OPN-NADPH oxidase-isoprostane signaling cascade. In the future, Dr. Towler will also be studying the osteogenic regulation of vascular calcification in murine models of diabetic vascular disease. Towler Lab 
Recent Publications Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005; May;115(5):1210-20. Sierra OL, Cheng SL, Loewy AP, Charlton-Kachigian N, Towler DA. MINT, the Msx2 interacting nuclear matrix target, enhances Runx2-dependent activation of the osteocalcin fibroblast growth factor response element. J Biol Chem. 2004 Jul 30;279(31):32913-23. Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab. 2004 May;286(5):E686-96. Shao JS, Cheng SL, Charlton-Kachigian N, Loewy AP, Towler DA. Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. J Biol Chem. 2003 Dec 12;278(50):50195-202. Hong C, Pilgram TK, Zhu F, Joe BN, Towler DA, Bae KT. Improving mass measurement of coronary artery calcification using threshold correction and thin collimation in multi-detector row computed tomography: in vitro experiment. Acad Radiol. 2003 Sep;10(9):969-77. Cheng SL, Shao JS, Charlton-Kachigian N, Loewy AP, Towler DA. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. J Biol Chem. 2003 Nov 14;278(46):45969-77. Bidder M, Shao JS, Charlton-Kachigian N, Loewy AP, Semenkovich CF, Towler DA. Osteopontin transcription in aortic vascular smooth muscle cells is controlled by glucose-regulated upstream stimulatory factor and activator protein-1 activities. J Biol Chem. 2002 Nov 15;277(46):44485-96. Epub 2002 Aug 27. Willis DM, Loewy AP, Charlton-Kachigian N, Shao JS, Ornitz DM, Towler DA. Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex. J Biol Chem. 2002 Oct 4; 277(40):37280-91. Bidder M, Loewy AP, Latifi T, Newberry EP, Ferguson G, Willis DM, Towler DA. Ets domain transcription factor PE1 suppresses human interstitial collagenase promoter activity by antagonizing protein-DNA interactions at a critical AP1 element. Biochemistry. 2000 Aug 1;39(30):8917-28. Newberry EP, Latifi T, Towler DA. The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter. Biochemistry. 1999 Aug 17;38(33):10678-90. Newberry EP, Latifi T, Towler DA. Reciprocal regulation of osteocalcin transcription by the homeodomain proteins Msx2 and Dlx5. Biochemistry. 1998 Nov 17;37(46):16360-8. Towler DA, Bidder M, Latifi T, Coleman T, Semenkovich CF. Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice. J Biol Chem. 1998 Nov 13;273(46):30427-34.
Division of Bone & Mineral Diseases
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